MINI REVIEW

published: 29 March 2019

doi: 10.3389/fped.2019.00110

Recent Trends in the Management of

Bladder Exstrophy: The Gordian Knot
Has Not Yet Been Cut
Martin Promm* and Wolfgang H. Roesch

Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center of Regensburg, Regensburg, Germany

Although enormous effort has been made to further improve the operative techniques
worldwide, the management of bladder exstrophy (BE) remains one of the most
significant challenges in pediatric urology. Today it is universally agreed that successful
and gentle initial bladder closure is decisive for favorable long-term outcome with regard
to bladder capacity, renal function and continence. Due to a number of reasons, including
a lack of comparable multicenter studies, a range of concepts is currently used to
achieve successful primary closure. We review the literature of the last 15 years on
the current concepts of bladder exstrophy repair with regard to the time of primary
closure (initial vs. delayed closure), the concepts of primary closure (single-stage vs.
staged approach; without osteotomy vs. osteotomy) and their outcomes. There is a
Edited by:
Ricardo González, worldwide lack of multicenter outcome studies with adequate patient numbers and
Kinder- und Jugendkrankenhaus Auf precisely defined outcome parameters, based on the use of validated instruments. The
der Bult, Germany
modern staged repair (MRSE) in different variations, the complete primary reconstruction
Reviewed by:
Peter Vajda,
of exstrophy (CPRE), and the radical soft-tissue mobilization (RSTM) had been the
University of Pécs, Hungary most extensively studied and reported procedures. These major concepts are obligatory
Imran Mushtaq,
stable now for more than 20 years. Nevertheless, there are still a lot of open-ended
Great Ormond Street Hospital,
United Kingdom questions e.g., on the potential for development of the bladder template, on continence,
*Correspondence: on long-term orthopedic outcome, on sexuality and fertility and on quality of life.
Martin Promm Management of BE remains difficult and controversial. Further, clinical research should
martin.promm@
barmherzige-regensburg.de
focus on multi-institutional collaborative trials to determine the optimal approach.
Keywords: bladder exstrophy, epispadias, urologic surgical procedures, delayed closure, osteotomy
Specialty section:
This article was submitted to
Pediatric Urology,
a section of the journal
INTRODUCTION
Frontiers in Pediatrics
Today the diagnosis of bladder exstrophy (BE) is usually made by prenatal ultrasound screening or
Received: 14 December 2018 by inspection after birth. In classic BE the bladder is completely opened in the lower abdomen so
Accepted: 06 March 2019 the edge of the inner surface of the bladder is fused to the abdominal skin. The evaginated bladder
Published: 29 March 2019
template is of different individual size. The mucosa of the bladder appears reddish and polyps may
Citation: be seen on it. The symphysis is widely separated. In male an epispadic urethral plate covers the
Promm M and Roesch WH (2019)
whole dorsum of the penis from the bladder template to the glanular grove (1). In females, the
Recent Trends in the Management of
Bladder Exstrophy: The Gordian Knot
clitoris is split and is located next to the open urethral plate. The vaginal opening appears narrow
Has Not Yet Been Cut. and is placed anteriorly on the perineum (1).
Front. Pediatr. 7:110. Often pediatricians are consulted to assess the neonates, to initiate further diagnostics and
doi: 10.3389/fped.2019.00110 to refer them to pediatric surgeons or pediatric urologists. Due to the very low prevalence

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Promm and Roesch Management of Bladder Exstrophy

and various treatment approaches of this disorder, most extreme stress during delivery, or to a surgical procedure,
physicians are not familiar with a standardized procedure. react to later noxious procedures with heightened behavioral
The aim of BE repair is successful bladder closure and penile responsiveness (13). The use of continuous caudal epidural
reconstruction in order to provide a capacious low-pressure analgesia allows application of local analgesia minimizing the use
and competent functioning reservoir as well as a good cosmetic of intravenous and oral opiate analgesia (14). It also helps to wean
appearance of the genitalia with unimpaired function and the babies from the respirator and decreases pediatric intensive
unobstructed urethra. By a successful primary closure normal care unit length of stay furthermore the minimal use of opiates
renal function should be preserved. may also decrease gastrointestinal motility disturbances (2). In
The management of BE remains one of the greatest challenges general neonatal epidural analgesia is feasible but it is a given fact
in pediatric urology. While it is universally agreed that successful that the application of an epidural catheter in a 6-weeks old infant
and gentle initial bladder closure is of utmost importance for is more reliable.
development of bladder capacity and continence there are still Also with regard to the development of renal function there is
numerous different concepts for the initial management of a more stabilized situation after the 6th week of life (15):
this condition (2). The main issues discussed are the time of
- Acid-base-regulation in the neonate is characterized by a
primary closure (immediate vs. delayed closure), the type of BE
reduced threshold for bicarbonate reabsorption. There is also
repair (complete or staged), and finally the need of symphysis
an inability to respond to an acid load, this improves by 4–6
approximation with or without pelvic osteotomy.
weeks postnatally.
Beyond doubt irrespective of the kind of reconstruction
- Renal concentration capacity is reduced in the first 2 month
technique worldwide attempts are made to reduce the morbidity
of live.
of management concepts.
- In the neonate glomerular filtration rate (GFR) is low and
doubles in the first 2 weeks and doubles again in the following
2–3 weeks.
TIMING
This immature situation of renal function in the newborn period
Regardless of the different surgical techniques, timing of primary means a high risk for long-term kidney function. Even marginal
closure still remains a matter of debate. The initial closure may iatrogenic fluid imbalance or temporary post-renal obstruction
be performed within the first 48–72 h of life (immediate) or at (e.g., stent or catheter obstruction) may provoke irreversible
∼6–12 weeks of age (delayed). renal impairment.
Early closure is recommended to prevent environmental Last but not least bonding after birth is of eminent importance
injury of the bladder mucosa (3). However, the impact of of developing infant’s self-regulation and further interaction to
early closure in respect of the incidence of inflammation, mother and father (16, 17). In particular, separation may delay
fibrosis, or even malignant changes remains unclear. Rösch and disrupt bonding in parents. Another advantage of delaying
et al. characterized the histology of polyps and mucosal biopsies surgery is initiating breastfeeding (18, 19). In addition, the time
excised during primary delayed surgery (4) and compared between birth and initial repair is useful to the parents to get
their findings with previous data concerning biopsies obtained psychological support if desired and to prepare themselves for the
during early closure in the neonate. In comparison to the procedure and the lengthy recovery period following.
specimens of newborns with BE (5) active inflammation was
more common but fibrosis and more severe inflammation was
not more frequent in delayed closure. Ferrara et al. suggested PREOPERATIVE MANAGEMENT
that some microscopic changes, such as squamous metaplasia,
In case of delayed management, only a few diagnostic measures
reverse to normal after bladder closure (6, 7). Literature on
are required preoperatively. Besides the ultrasound of the
mucosal changes in early life in BE is rare. Including data of
upper urinary tracts and the hips an echocardiography is
subsequent series (8, 9), there is no advice for histologically or
recommended, recent studies indicate that there is an increased
immunohistochemically detectable premalignant changes after
risk of associated congenital heart failures in BE patients (20).
the interim of 6–8 weeks and in comparison to early bladder
Further diagnostics like MRI or computer tomography are not
closure neither fibrosis nor more severe inflammation seems to
necessary. Until surgery the bladder template is covered with
be more frequent after that time.
topical ointment compresses against inflammation and alteration
Anesthesia and analgesia are challenging in primary BE
of the mucosa (1). There is no need for an extended hospital stay
repair especially in early closure. Some factors associated with
after delivery or even stay on the intensive care unit. Antibiotic
perioperative cardiac arrest have been identified (10, 11). It was
prophylaxis is not necessary and not recommended in order to
found that the largest number of perioperative complications
avoid development of resistance or topical fungal infection.
occurred in newborns (10, 12). Further, on there is a higher
oxygen uptake rate in newborns. This means a severely increased
risk of hypoxia damage in cases of circulation or ventilation MAIN SURGICAL CONCEPTS
problem during surgery or post-operatively. One of the most
important determinants of successful bladder closure is effective Already at the beginning of the twentieth century there are first
local analgesia. There is evidence that neonates exposed to reasonable attempts to treat this defect surgically. Since the 50’s

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Promm and Roesch Management of Bladder Exstrophy

numerous different concepts are introduced to reconstruct BE TABLE 1 | Wide range of continence rate of the different approaches depending
under functional and aesthetic aspects. on definition of continence and observation period.

Three of them has been the most extensively studied and Approach Continence rate (%) Literature
reported procedures.
The modern staged repair (MSRE) (21), the complete primary MSRE 74 Gearhart et al. (30)
reconstruction of bladder exstrophy (CPRE) (22) and the radical 62 Gupta et al. (31)
soft tissue mobilization (RSTM) (23). 22 Dickson et al. (32)
The traditional staged reconstruction popularized by CPRE 80 Grady et al. (22)
Gearhart and Jeffs has been a standard approach for many 74 Hammouda et al. (33)
years (1, 21). The so-called “modern staged repair” (MSRE) 23 Arab et al. (27)
is currently advocated as a modification by John Gearhart. He RSTM 73 Kelly et al. (23)
made this three-stage concept popular worldwide (1, 24). The 70 Jarzebowski et al. (34)
bladder template the posterior urethra and the abdominal wall 33–67 (female) Cuckow et al. (35)
are closed within the first 2 days of life and the pelvic ring is 44–81 (male)
adapted. Epispadias repair follows at the age of 6–9 months. In
females, genital reconstruction is mostly included in the first
operative procedure. As a third step, bladder neck reconstruction
and simultaneously an antireflux plasty are performed when around the new created posterior pelvic urethra to work as a
bladder capacity reaches a minimum of 85 cc. and the child is continence mechanism. No osteotomy is performed since RSTM
ready for continence training (1). allows sphincter reconstruction and abdominal wall closure
An antireflux plasty is always conducted with the bladder neck without tension.
reconstruction (1). RSTM is an anatomical reconstruction of BE generally
Currently multiple variations of bladder neck reconstruction performed as part of a two-staged strategy following successful
within this concept are established in different parts of the neonatal closure. Complete delayed bladder closure with RSTM
world. The restriction of all the above named modifications is is a recently published modification of this concept (6).
that they can create essentially only a kind of obstruction of However, the Kelly repair remains a long and technically
the bladder neck instead of a functional continence mechanism. challenging procedure even in experienced hands with a very
Moreover, obstruction is not necessary for bladder growth, quiet possible risk of ischemic damage of the erectile tissue (28).
the contrary, initial bladder neck surgery might have negative Further on, leaving the symphysis without adaptation poses a
effects on the development of a functional bladder (8). certain risk with regard to the long-term abdominal wall stability
As a sort of striking a new path Grady and Mitchell introduced and the gynecological outcome, during pregnancy as well as in
the complete primary repair of bladder exstrophy (CPRE) terms of early prolapse of uterus (29).
in hope it would more closely mimic the normal anatomy
and therefore physiology of the normal bladder (22, 25). This CONTINENCE RESULTS
approach includes bladder closure and reconstruction of the
penis using the penile disassembly technique. This procedure Although there are numerous publications on BE, most of the
is implemented on the basic concept that the primary defect outcome are recorded retrospectively as single-center or single-
of bladder exstrophy results from on anterior herniation of the surgeon-studies. Different definitions observation periods, end-
bladder. It hence appears to be necessary to treat the bladder, points, and successful outcome, in particular the definition of
the bladder neck and the urethra as one entity in order to “continence” and possibly further surgeries lead to quit different
transfer them successfully and permanently into the pelvis. The results (Table 1). Although first results of all approaches show a
penile disassembly technique is performed simultaneously with very promising high rate of continence, long-term studies that
bladder neck reconstruction (26). Unfortunately in the long-term must mean at least 20 years of follow-up (36) reveal disillusioning
follow-up in numerous cases a bladder neck reconstruction was results. This fact also seems in our experience to be more realistic.
necessary to gain social continence (27). Further on concern is Moreover, Woodhouse et al. postulate that more than 80% of the
raised for the risk of future detrusor underactivity as well as reconstructed children can achieve continence, but there is some
erectile function due to the “unimpeded radical mobilization” evidence that in 70% this is lost with time (36).
of the bladder-urethral plate complex in the direction of the
pelvis (25).
The radical soft tissue mobilization (RSTM) introduced by EPISPADIAS REPAIR
Kelly (23) may be considered as the so far most consequent
The following procedures are the basis to ensure a functional and
concept off the classical bladder neck reconstruction. The
cosmetically acceptable outcome (1):
unique aspect of this technique is the dissection especially of
the pelvis and the corpora cavernosa from the ischiopubic - The remove of dorsal chordee
rami including the periosteum with the attachments of the - Reconstruction of the urethra
voluntary and unvoluntary sphincter muscles and the pudendal - Glandular reconstruction
vessels and nerves (23). These muscles are used as a wrap - Penile skin closure

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Promm and Roesch Management of Bladder Exstrophy

TABLE 2 | Outcome of symphyseal approximation with and without osteotomy.

Literature N= Median age at Type of osteotomy Symphysis with cm (range)

investigation

Kaar et al. (44) 13 (11 m., 2f.) 24 years (17–36 year) Posterior osteotomy 5.8 cm (4.1–11.2)
Satsuma et al. (45) 9 (3m., 6f.) 8 years (5 month−17.5 year) Anterior or combined osteotomy (n = 3) 3.75 cm (1–7)
Posterior osteotomy (n = 6)
Castagnetti et al. (46) 14 9.7 years (3.1–17.8 year) No osteotomy (n = 6) Osteotomy 4.9 cm (2.4–6.6)
various types (n = 8) 4.2 cm (2.5–10.1)
Kertai et al. (43) 17 (14 m., 3f.) 18.2 years (13–28 year) Symphysis adaptation without osteotomy 5.1 cm (2.8–8.5)

Silver was able to show that the corpora cavernosa in BE are very pelvic attachment (39). Skin and tissue retraction in the mons
much shorter than in age-matched controls (37). The reduced pubis area is cosmetically improved by mobilizing adjacent
length of the penis is thus primarily an acquired deficit of corpora inguinal tissue and rotating it medially into the affected area.
cavernosa tissue and not only a consequence of the chorda and In about 2/3 of these patients vaginoplasty is advisable (1).
the bilateral fixation to the ascending pubic rami, which was Episiotomy or an introitusplasty using a triangular skin-flap
assumed for a long time. (Fortunoff-flap) can be performed to prevent repeated dilatations
Ransley introduced the concept of releasing dorsal chordee by during childhood (1, 40). This should be done just in before or
incision and dorso-medial anastomosis of the corpora cavernosa during puberty.
above the urethra (38). Today, the Cantwell-Ransley technique is
a modification and further development in which a very much NEED OF OSTEOTOMIES
more effective relocation of the urethra between or below the
corpora is possible by complete mobilization of the urethral plate The role of osteotomy is still a main topic in initial bladder
from the corpora (Figure 1). closure. For a long time osteotomy was regarded essential for
The characteristic feature of the Mitchell technique is the a successful outcome. But there are also reports confirming no
complete dissection of the penis into 3 parts (26): The urethral difference in success of bladder closure (1, 41, 42). However,
plate, the right corpus cavernosum with hemiglans and the left it is known that symphysis diastasis recurs after all commonly
corpus cavernosum with hemiglans (26). After tubularization of used pelvic closure techniques (43). There are only a few
the urethral plate, it is positioned ventrally between the corpora studies dealing with pubic diastasis after various types of pelvic
cavernosa. If the urethra is too short, the neomeatus hast to be osteotomy in a reasonable follow-up (36–39). According to these
positioned on the ventral part of the penis. Hence, most patients data the distance of recurrent mean pubic diastasis is not differing
require an additional procedure for hypospadias repair. Further relevant in the long-term with and without osteotomy (Table 2).
on concern is raised for future erectile function due to shearing Castagnetti et al. compared patients after initial closure with and
and stretch injury to the nerve fibers during complete penile without osteotomy prospectively (46). In the long-term follow up
disassembly (25). they found no significant difference in the wide of pubic diastasis,
Perineal dissection during the RSTM allows complete in the number of exstrophy-related surgical procedures, in the
exposure of the corpora cavernosa (23). Incision of the incontinence rate and in the number of patients needing clean
periosteum of the ischio-pubic rami until the Alcock’s canal intermitting catheterization for bladder emptying (46). Kertai
allows a full mobilization of both corpora. Mostly urethral et al. was able to show that despite BE-specific hip morphology,
plate is short and would retract the corpora and shorten the long-term hip function was not impaired in adult adolescent
penis. Therefore, in most cases distal urethra is disconnected patients after symphysial approximation without osteotomy
from the glans and placed in hypospadic position. After in infancy. The symphysis diastasis after this procedure was
readaptation the corpora were anchored to the neosymphysis also comparable to available post-osteotomy data in the long-
using unabsorbable sutures. term (43). In a case series published by Mushtaq et al. (2),
Owing to extensive mobilization, all techniques of epispadias primary bladder closure without osteotomy and post-operative
repair have in common that they require a very meticulous immobilization was successful in 70 of 74 patients (95%) in
dissection in the anatomical layers using magnification glass in respect to bladder closure. In our department pelvic ring closure
order to maintain the blood and nerve supply of the individual could be achieved during the last 15 years without osteotomy in
structures to avoid erectile dysfunction and corporal atrophy. all infants with classical BE younger than 8 weeks (1, 41).
Nowadays, the reconstruction of female genital becomes less In female patients symphysis approximation may prevent
invasive. The split clitoris is usually left untouched to protect uterine prolapse regardless of the type pelvic adaptation (with or
the delicate nerve supply and to avoid scaring caused by later without osteotomy) (1).
re-dehiscence of the symphysis. Recently Benz et al. were able Nevertheless, based on the available literature and
to show that contrary to the corpora cavernosa in boys, girls contemporary variability in worldwide practice, it would
with BE have the majority of the clitoral body anterior to the appear that there is currently no consensus regarding the

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Promm and Roesch Management of Bladder Exstrophy

understanding the preconditions for development of bladder-

function and -capacity in BE.
Beside, further immuno-histologic studies of the bladder
template, genetics will help to assess the prognosis in a realistic
way. The systematic and comprehensive application of modern
molecular genetic techniques in large BE cohorts has started
to identify putative disease causing genes and regions in the
genome for Mendelian and multifactorial BE phenotypes (48).
Such studies can offer new diagnostics, and provide a more exact
estimation of recurrence risk in affected families (48). Parallel
functional analysis of the respective embryonic pathways offers
a more profound understanding of the molecular mechanisms
underlying the embryology of the urogenital tract (48). Moreover,
understanding the respective embryonic pathways can help to
explain related genitourinary malformations (49).
Tissue engineering aims to develop alternatives for current
techniques in which intestinal tissue is used for patients with
FIGURE 1 | Bladder after primary closure drained by a suprapubic and two
inadequate development of bladder capacity. Recent studies
ureteral catheters. Four sutures are prepared for approximation of the
separated corpora carvernosa over the tubularized urethra with an indwelling using tissue engineered extracellular matrices or acellular
stent. The corpora are rotated laterally to correct the dorsal deviation scaffolds with growth factor in animal models are promising
of the penis. (50, 51). However, there are scores of open issues which need to
be fully clarified and defined before tissue-engineering in urology
progresses from bench to bedside in BE-reconstruction.
Muscle-derived stem cells (MDSC) may offer further benefits
necessity of osteotomy in primary BE repair. Although not in regenerative medicine (52). Several clinical studies have
universal, most would agree on the efficacy of osteotomy in redo evaluated the effect of cell therapy with autologous myoblasts
cases (47). in the treatment of urinary incontinence, and have shown
promising results (53, 54). Against this background MDSC
CURRENT RESEARCH GAPS AND therapy might represent a minimally-invasive procedure also in
POTENTIAL FUTURE DEVELOPMENTS the treatment of patients with isolated epispadias in the near
future. Latest studies are promising to generate differentiated
A critical look into the historical data indicates that almost urothelium from stem cells isolated from the urine. Urothelium
nothing is new in the philosophy and treatment of BE since more obtained this way seems to be comparable with native urothelium
than one century ago. Nevertheless, due to the benefits of new and provides a valuable tool for reconstruction of the urinary
technological developments there was an appreciable progress in tract as well as offers the chance for further studies in urothelial
BE reconstruction during the last decades of the last century. All dysfunction (55).
these major concepts are obligatory stable now for more than Management of BE remains difficult and controversial.
20 years and ensure a safe primary bladder closure including Further basic and clinical research should focus on
an appealing appearance of the genitalia in experienced hands. multi-institutional collaborative trials to determine the
Apart from that, there are still a lot of open ended questions optimal approach. Irrespective of that multidisciplinary
e g., on the potential for development of bladder capacity, on ideation is in demand to generate new functional reconstruction
continence, on long-term orthopedic outcome, on sexuality and concepts for this condition.
fertility and on quality of life.
First of all further clinical studies should focus on multi-center AUTHOR CONTRIBUTIONS
prospective trials with exactly defined outcome parameters to
find an optimal management (29). In addition basic research is All authors contributed conception and design of the
necessary to elucidate the morphological changes in the pattern review, wrote sections of the manuscript, contributed to
of detrusor muscle and epithelium to establish a basis for manuscript revision, read, and approved the submitted version.

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